In the US, asbestos causes ˜2-3,000 malignant mesothelioma (MM) deaths/year, and contributes to an even larger number of lung carcinomas because asbestos has a synergistic carcinogenic effect with cigarette smoke. The latency of 30-50 years from the time of exposure to tumor development could potentially allow time for intervention to block the presently unclear mechanism(s) that trigger asbestos-induced carcinogenesis (Carbone M & Bedrossian C W (2006) The pathogenesis of mesothelioma. (Translated from eng) Semin Diagn Pathol 23(1):56-60 (in eng)).
Asbestos refers to a family of mineral fibers that includes crocidolite, often considered the most oncogenic type. Since asbestos does not induce malignant transformation of primary human mesothelial cells (HM) directly, indirect mechanisms of carcinogenesis have been investigated. Inhaled asbestos fibers become entrapped in the lung and some migrate through the lymphatics to the pleura.
Indeed, cancer often arises in the setting of chronic inflammation and it has been suggested that asbestos-induced inflammation might be somehow linked to asbestos carcinogenesis (Quinlan T R, Marsh J P, Janssen Y M, Borm P A, & Mossman B T (1994) Oxygen radicals and asbestos-mediated disease. (Translated from eng) Environ Health Perspect 102 Suppl 10:107-110 (in eng); Choe N, et al. (1997) Pleural macrophage recruitment and activation in asbestos-induced pleural injury. (Translated from eng) Environ Health Perspect 105 Suppl 5:1257-1260 (in eng)).
The mechanisms that trigger the chronic inflammatory response seen in the lungs of asbestos-exposed individuals and in many MM patients are unknown. Macrophages play an important role in this process by releasing mutagenic reactive oxygen species (ROS) and cytokines that support inflammation. Among these cytokines, TNF-α has been identified as a critical mediator of the pathogenesis of asbestos-related disease. TNF-α has been linked to tumor promotion, to fibrosis and asbestosis, to asbestos carcinogenesis and to MM.
Asbestos is cytotoxic. Most HM exposed to asbestos die within 24-48 hrs. The mechanisms of asbestos-induced HM cell death and the possible link between cytotoxicity and carcinogenesis is unclear.